Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly [version 1; peer review: 2 approved]

Abstract

Protein ubiquitylation is essential for the maintenance of cellular homeostasis. E3 ubiquitin ligases are key components of the enzymatic machinery catalyzing the attachment of ubiquitin to substrate proteins. Consequently, enzymatic dysfunction has been associated with medical conditions including cancer, diabetes, and cardiovascular and neurodegenerative disorders. To safeguard substrate selection and ubiquitylation, the activity of E3 ligases is tightly regulated by post-translational modifications including phosphorylation, sumoylation, and ubiquitylation, as well as binding of alternative adaptor molecules and cofactors. Recent structural studies identified homotypic and heterotypic interactions between E3 ligases, adding another layer of control for rapid adaptation to changing environmental and physiological conditions. Here, we discuss the regulation of E3 ligase activity by combinatorial oligomerization and summarize examples of associated ubiquitylation pathways and mechanisms.